Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation

Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is caused in almost all cases by homozygous intronic expansions resulting in the loss of frataxin, a mitochondrial protein conserved through evolution, and involved in mitochondrial iron homeostasis. Yeast knockout models, and his...

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Bibliographic Details
Published in:Human molecular genetics 2000-05, Vol.9 (8), p.1219-1226
Main Authors: COSSEE, M, PUCCIO, H, GANSMULLER, A, KOUTNIKOVA, H, DIERICH, A, LEMEUR, M, FISCHBECK, K, DOLLE, P, KOENIG, M
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biological and medical sciences
Decidua - cytology
Decidua - pathology
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Embryo, Mammalian - pathology
Exons
Female
Fetal Death - genetics
Frataxin
Frda gene
Friedreich Ataxia - genetics
Genotype
Homozygote
Humans
Introns
Iron - metabolism
Iron-Binding Proteins
Iron-Sulfur Proteins - deficiency
Iron-Sulfur Proteins - genetics
Medical sciences
Mice
Mice, Knockout
Necrosis
Neurology
Phenotype
Phosphotransferases (Alcohol Group Acceptor) - deficiency
Phosphotransferases (Alcohol Group Acceptor) - genetics
Pregnancy
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Summary:Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is caused in almost all cases by homozygous intronic expansions resulting in the loss of frataxin, a mitochondrial protein conserved through evolution, and involved in mitochondrial iron homeostasis. Yeast knockout models, and histological and biochemical data from patient heart biopsies or autopsies indicate that the frataxin defect causes a specific iron-sulfur protein deficiency and mitochondrial iron accumulation leading to the pathological changes. Affected human tissues are rarely available to further examine this hypothesis. To study the mechanism of the disease, we generated a mouse model by deletion of exon 4 leading to inactivation of the Frda gene product. We show that homozygous deletions cause embryonic lethality a few days after implantation, demonstrating an important role for frataxin during early development. These results suggest that the milder phenotype in humans is due to residual frataxin expression associated with the expansion mutations. Surprisingly, in the frataxin knockout mouse, no iron accumulation was observed during embryonic resorption, suggesting that cell death could be due to a mechanism independent of iron accumulation.
ISSN:0964-6906
1460-2083
1460-2083
DOI:10.1093/hmg/9.8.1219